KR20240006600A - dosing regimen - Google Patents

Abstract

The present invention relates to N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl) Dosage regimens and combinations comprising pyridine-3-carboxamide or pharmaceutically acceptable salts thereof, and treatment of breakpoint cluster region-abelson protein (BCR-ABL) mediated diseases or disorders It relates to its use in .

Description

dosing regimen

The present invention relates to N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl) Dosage regimens and combinations comprising pyridine-3-carboxamide or pharmaceutically acceptable salts thereof, and treatment of breakpoint cluster region-abelson protein (BCR-ABL) mediated diseases or disorders It relates to its use in .

The tyrosine kinase activity of the ABL1 protein is generally tightly regulated, in which the N-terminal cap region of the SH3 domain plays an important role. One regulatory mechanism involves the N-terminal cap glycine-2 residue being myristoylated and then interacting with the myristate binding site within the SH1 catalytic domain. The hallmark of chronic myeloid leukemia (CML) is the Philadelphia chromosome (Ph), formed by a t(9,22) reciprocal chromosomal translocation in hematopoietic stem cells. This chromosome carries the BCR-ABL1 oncogene, which encodes a chimeric BCR-ABL1 protein that lacks the N-terminal cap and has a constitutively active tyrosine kinase domain.

Drugs that inhibit the tyrosine kinase activity of BCR-ABL1 through an ATP-competitive mechanism, such as Gleevec® / Glivec® (imatinib), Tasigna® (nilotinib), and Sprycel® (dasatinib), are effective in treating CML, but some Patients relapse due to the emergence of drug-resistant clones where mutations in the SH1 domain impair inhibitor binding. Tasigna® and Sprycel® maintain efficacy against many Gleevec-resistant mutant forms of BCR-ABL1, but the mutation in which the threonine-315 residue is replaced by isoleucine (T315I) remains insensitive to all three drugs and causes CML patients It may lead to resistance to therapy. Therefore, suppressing BCR-ABL1 mutations such as T315I still remains an unmet medical need. In addition to CML, the BCR-ABL1 fusion protein causes a certain percentage of acute lymphoblastic leukemia, and drugs targeting ABL kinase activity are also useful for this indication.

Agents targeting the myristoyl binding site (so-called allosteric inhibitors) have the potential to treat BCR-ABL1 disorders (Zhang et. al., Targeting BCR-ABL by combining allosteric with ATP-binding-site inhibitors .Nature 2010;463:501-6]). To prevent the emergence of drug resistance due to the use of ATP inhibitors and/or allosteric inhibitors, combination therapies using both types of inhibitors may be developed for the treatment of BCR-ABL1-related diseases or disorders. In particular, there is a need for small molecules or combinations thereof that inhibit the activity of BCR-ABL1 and BCR-ABL1 mutants through the ATP binding site, the myristoyl binding site, or a combination of the two sites.

Provided herein are BCR-ABL inhibitors with activity at a site different from the currently available ATP site second- and third-generation TKIs, which may suggest an alternative mechanism of inhibition and, when used in combination, inhibit the presence of point mutation(s). Because acquisition is at one of the above binding sites, the development of resistance can be prevented and thus address unmet medical needs, including the treatment of BCR-ABL mediated diseases or disorders, including CML, ALL and AML.

Described herein are methods of treating a subject using a BCR-ABL inhibitor, particularly Compound I, for use in treating a BCR-ABL mediated disease or disorder. Also described herein is a method of treating a BCR-ABL mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a BCR-ABL inhibitor, particularly Compound I, administered without food. will be.

Compounds of formula I: N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazole-5- 1) Pyridine-3-carboxamide:

[Formula I]

or Compound I, preparation of Compound I, and pharmaceutical compositions of Compound I were originally described as Example 9 in WO 2013/171639 A1. Compound I is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl) Also known as nicotinamide, or asciminib. (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide ( Bottom, left structure) is (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazole-3 -1) is a tautomer of nicotinamide (structure below, right), and vice versa:

.

WO 2013/171639 A1 provides a method for treating diseases in which Compound I responds to inhibition of the tyrosine kinase enzyme activity of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins, especially BCR-ABL1. It is described as useful.

Further provided herein are specific dosage regimens for the methods or uses of the BCR-ABL inhibitors described herein, particularly Compound I.

Additionally, pharmaceutical combinations comprising a) Compound I and b) at least one additional therapeutic agent, optionally in the presence of a pharmaceutically acceptable carrier, for use in the treatment of a BCR-ABL mediated disease or disorder and comprising the same. Pharmaceutical compositions are described herein. Preferably, said at least one additional therapeutic agent is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib; More preferably, it is imatinib. In one embodiment, the pharmaceutical combination is administered with food, preferably a low-fat meal.

Additional features and advantages of the described methods and uses will become apparent from the detailed description that follows.

Figure 1 shows (A) dissolution and (B) penetration through artificial lipid membranes of asciminib (2 In vitro flow studies assessing the impact of (mimicking conditions) are presented.
Figure 2 provides a schematic overview of the treatment protocol detailed in Example 2.
Figure 3 shows arithmetic mean (SD) plasma concentration-time profiles for (A) aciminib and (B) imatinib plus aciminib alone and aciminib + imatinib (DDI group).
Figure 4 shows the arithmetic mean (SD) plasma concentration-time profile of asciminib when administered under fasting, low-fat meal, and high-fat meal conditions (FE group).

Currently, Compound I is being studied as a TKI-combination therapy with the established CML treatments imatinib, nilotinib, or dasatinib in a phase 1, first-in-human, dose-finding study (NCT02081378) in patients with CML, and as a single agent, in a phase 3 randomized controlled trial. Patients who failed to achieve a deep molecular response (defined as a BCR-ABL1 transcript value ≤0.01% in the International Reporting Scale [IS]) with first-line imatinib as a single agent and for more than 1 year in (ASCEMBL; NCT03106779) It is being studied as an add-on therapy to first-line imatinib in a phase 2 study (ASC4MORE; NCT03578367).

For single agent Compound I, the recommended phase 3 dose in CML patients is 40 mg twice daily (fasting; the maximum tolerated dose in CML patients is not reached with doses up to 200 mg twice daily). In the phase 3 ASCEMBL study in chronic phase CML patients (without BCR-ABL1 T315I mutation) previously treated with 2 or more prior TKIs, Compound I monotherapy (40 mg twice daily) achieved the primary endpoint at 24 weeks. It showed a statistically significant and clinically meaningful superiority compared to the ATP-competitive BCR-ABL1 inhibitor bosutinib (500 mg once daily) in major molecular responses (BCR-ABL1≤0.1% in IS) (25.5%). vs. 13.2%; difference 12.2%, 95% CI, 2.19 to 22.3: P=0.029), with a good safety profile.

The combination of asciminib plus imatinib was well tolerated and showed promising preliminary efficacy in a first-in-human phase 1 study in patients with CML resistant or intolerant to other TKIs. In a preliminary PK analysis in this population evaluating the potential drug-drug interaction (DDI) between asciminib and imatinib, asiminib 40 mg once daily + imatinib 400 mg once daily with food ) (due to the better tolerability of imatinib when taken with food) was found to provide assiminib exposure comparable to that achieved with the recommended asiminib monotherapy dose in the fasting state. The first-in-human study used the initial asciminib tablet formulation, which showed a slight decrease in asciminib bioavailability when taken with food compared to the fasted state (30-31% reduction in exposure with a low-fat meal; 30-31% reduction in exposure with a high-fat meal). exposure decreased by 63-64%). For commercial use of Compound I, a slightly modified tablet formulation (final marketed image (FMI)) was developed to ensure scalability to commercial batch sizes. Therefore, further investigation is warranted to better characterize the DDI between imatinib and Compound I and to better establish the food effect (FE) for the commercial tablet formulation of Compound I.

Described herein is a method of treating a BCR-ABL mediated disease or disorder, comprising administering to a subject in need thereof an effective amount of Compound I, or a pharmaceutically acceptable salt thereof.

Accordingly, in one aspect, a method of treating a BCR-ABL mediated disease or disorder is provided, comprising administering to a subject in need thereof an effective amount of Compound I, or a pharmaceutically acceptable salt thereof, without food. . In a further embodiment, administering Compound I or a pharmaceutically acceptable salt thereof with food results in reduced bioavailability in the subject compared to administering Compound I or a pharmaceutically acceptable salt thereof without food. In a further embodiment, the AUC is reduced by 30% to 60% when Compound I or a pharmaceutically acceptable salt thereof is administered with food compared to when administered without food.

In another aspect, a method of treating a BCR-ABL mediated disease or disorder is provided, comprising providing to a subject in need thereof an effective amount of Compound I or a pharmaceutical thereof for use in the treatment of a BCR-ABL mediated disease or disorder. administering a pharmaceutical combination comprising an acceptable salt and an effective amount of at least one additional therapeutic agent (optionally in the presence of a pharmaceutically acceptable carrier) and pharmaceutical compositions comprising them. Preferably, said at least one additional therapeutic agent is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib; More preferably, it is imatinib. In a further embodiment, the pharmaceutical combination is administered with food, preferably a low-fat meal. In a further embodiment, administration of the pharmaceutical combination with food increases the systemic exposure (AUCinf and AUClast) of Compound I by about 2-fold and increases the Cmax of Compound I by about 1.6-fold compared to Compound I taken with food.

Justice

To make this document easier to understand, certain terms are first defined. Additional definitions are provided throughout this document.

As used herein, the term “comprising” includes “including” as well as “consisting of,” e.g., a composition “comprising” It may consist of only, or it may include additional things, for example,

As used herein, the articles “a” and “an” refer to one or more (e.g., at least one) of the grammatical objects of the article.

The term “or” is used herein to mean, and is used interchangeably with, the term “and/or” unless the context clearly indicates otherwise.

As used herein, the term “about” and its grammatical equivalents with respect to a reference numeric value can include the numeric value itself and a range of values ±10% from that numeric value. For example, an amount of “about 10” includes 10 and any amount from 9 to 11. For example, the term "about" in reference to a reference numerical value also includes ±10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of that value. The range may be included. In some cases, a generally stated numerical value may be “about” that numerical value without specifically mentioning the term “about.”

As used herein, the term "baseline" means, according to the methods and uses described, prior to treatment, e.g., prior to administration of the compound, e.g., Compound I, optionally in combination with at least one additional therapeutic agent. Refers to one or more parameters related to the condition or condition of a subject, such as the extent of a disease, or the condition of a patient, observed prior to administration.

As used herein, the term “administering” with respect to a compound, e.g., Compound I (optionally in combination with one or more additional therapeutic agents), is used to refer to delivery of such compound by any route of delivery. . Such delivery may be, for example, intravenous or oral administration. Such delivery may also be, for example, subcutaneous administration.

As used herein, the terms “administered with food” or “with food” or “feeding state” or “feeding conditions” or “feeding” refers to food, e.g., any solid or liquid food (calorie content refers to the state of ingestion. The term “food” refers to food and includes raw materials and ingredients, e.g., as defined in section 201(f) of the Federal Food, Drug, and Cosmetic Act. Preferably, the food is a solid food with sufficient bulk and fat content to prevent rapid dissolution and absorption in the stomach. A dose of Compound I may be administered to the subject, for example, between 30 minutes before and about 2 hours after eating food. In embodiments, food is consumed about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes prior to Compound I administration. Preferably, administration of Compound I may occur immediately after ingestion of food up to about 30 minutes after ingestion.

As used herein, the term “no food” or “fasting condition” or “fasting condition” or “fasting” refers to, for example, eating solid food for at least about 1 hour before about 2 hours after eating solid food. It refers to the state of not being consumed. In some embodiments, food has not been consumed for about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes prior to administration of Compound I. In some embodiments, food is not consumed for about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes following administration of Compound I.

As used herein, the term “low-fat meal” refers to that defined by the U.S. Food and Drug Administration in the Draft Guidance on Assessing the Effects of Food on Drugs in INDs and NDAs (FDA 2019) (see also Assessing the Effects of Food on Drugs in Investigational New Drug Applications and New Drug Applications-Clinical Pharmacology Considerations; Draft Guidance for Industry; Availability, 84 Fed. Reg. 6151 (February 26, 2019)]. An example of a low-fat meal is one with less than 20% fat and about 400 calories.

As used herein, the terms “administered with a low-fat meal” or “with a low-fat meal” are defined to mean the condition in which a low-fat meal is consumed along with the administration of Compound I within a specified time prior to administration of Compound I. do. A dose of Compound I may be administered to the subject, for example, between 30 minutes before and about 2 hours after eating a low-fat meal. In embodiments, the low-fat meal is consumed about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes prior to Compound I administration. Preferably, administration of Compound I may occur immediately after ingestion of a low-fat meal up to about 30 minutes after ingestion.

As used herein, the term “pharmaceutically acceptable” means a non-toxic substance that does not substantially interfere with the effectiveness of the biological activity of the active ingredient(s).

As used herein, the term “patient” is used interchangeably with the term “subject” and includes any human or non-human animal. The term “non-human animal” includes all vertebrates, including mammals and mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, and the like. In certain embodiments, the compositions, methods and uses described herein relate to human patients or human subjects.

As used herein, a subject is “in need of” treatment if he or she is suffering from a condition of interest (i.e., disease, disorder, or syndrome) and would benefit biologically, medically, or in terms of quality of life from treatment.

As used herein, the term “BCR-ABL mediated disease or disorder” refers to a non-malignant disease or disorder, such as CNS diseases, especially neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), motor neuron diseases (amyotrophic Diseases or disorders associated with abnormally activated kinase activity of wild-type ABL1, including lateral sclerosis), muscular dystrophy, autoimmune and inflammatory diseases (diabetes and pulmonary fibrosis), viral infections, and prion diseases. Preferably, the disease or disorder is a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

GLEEVEC® (imatinib mesylate) is indicated for the treatment of patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumor (GIST). It is also indicated for the treatment of adult patients following complete gross resection of KIT(CD117)-positive GISTs. This also applies to adult and pediatric patients newly diagnosed with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase (CP), accelerated phase (AP), or blast phase (BC) after failure of interferon-alpha therapy. Indicated for the treatment of patients with Ph+ CML. It can also be used as a targeted medicine for the treatment of rare diseases with limited treatment options: relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); Myelodysplastic/myeloproliferative disease (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene rearrangement; D816V Aggressive systemic mastocytosis (ASM) without c-KIT mutation or with unknown c-KIT mutation status; For patients with HES and/or CEL with negative or unknown FIP1L1-PDGFRα fusion kinase and hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/ CEL); and unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP).

TASIGNA® (nilotinib) is indicated for the treatment of adult patients with newly diagnosed chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). It is indicated for the treatment of adults who no longer benefit from or are intolerant to other treatments, including imatinib (GLEEVEC), or who have taken but may be unable to tolerate other treatments, including imatinib (GLEEVEC). can be used to

SPRYCEL® (dasatinib) is used to treat adults with newly diagnosed chronic phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) who no longer benefit from or are intolerant to other treatments. It is a prescription drug that is also used for ALL patients.

BOSULIF® (bosutinib) is indicated for the treatment of adults with newly diagnosed chronic phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) and for the treatment of adults who no longer benefit from or are intolerant of other treatments. It is a prescription drug that is also used for ALL patients.

The term “treatment” refers to the administration of Compound I, as described herein, or its pharmaceutically acceptable content to warm-blooded animals, particularly humans, in need of such treatment, e.g., for the purpose of curing a disease or effecting disease regression or delaying the progression of a disease. and therapeutically administering a possible salt, or a combination of Compound I or a pharmaceutically acceptable salt thereof with one or more additional therapeutic agents. The terms “treat,” “treating,” or “treatment,” with respect to any disease or disorder, refer to a method that improves the disease or disorder (e.g., slows or arrests the development of the disease or at least one of its clinical symptoms). refers to preventing or delaying the onset, progression, or progression of a disease or disorder. More specifically, said at least one additional therapeutic agent is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib; More preferably, it is imatinib.

The terms “treat,” “treating,” or “treatment” include therapeutic treatment, prophylactic treatment, and applications that reduce the risk of a subject developing a disorder or other risk factor. Treatment does not require complete cure of the disorder and includes reduction of symptoms or underlying risk factors.

The term “treating” refers to the use of a compound, e.g. Compound I, to prevent or delay the onset of symptoms, complications or biochemical manifestations of a disease, condition, disorder or syndrome (e.g. a BCR-ABL mediated disease or disorder). Optionally administered in combination with one or more additional therapeutic agents to alleviate symptoms or arrest or inhibit further development or manifestation of the disease, condition, disorder or syndrome.

As used herein, the term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each ingredient is compatible with the other ingredients of the pharmaceutical formulation and can be used in humans and animals without undue toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications commensurate with a reasonable benefit/risk ratio. “Pharmaceutically acceptable” in the sense that it is suitable for use in contact with tissues or organs. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005]; Handbook of Pharmaceutical Excipients, 6th ed. ; Rowe et al. , Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009]; Handbook of Pharmaceutical Additives, 3rd ed. ; Ash and Ash Eds.; Gower Publishing Company: 2007]; Pharmaceutical Preformulation and Formulation, 2nd ed. ; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

As used herein, the term “BCR-ABL inhibitor” is a compound that inhibits the tyrosine kinase enzyme activity of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins, particularly BCR-ABL1.

As used herein, “compound of formula I” or “compound I” are used interchangeably and refer to a compound having the structure shown below, known in the art and described in WO2013/171639, incorporated by reference in its entirety. ) can be synthesized using the procedure described in:

.

Any formula given herein is intended to represent unlabeled as well as isotopically labeled forms of the compound. Isotopically labeled compounds have the structures depicted by the formulas given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the invention include, for example, isotopes of hydrogen, carbon, nitrogen, and oxygen, such as ³ H, ¹¹ C, ¹³ C, ¹⁴ C, and ¹⁵ N. Accordingly, the method of the present invention is a compound comprising one or more of the above isotopes, including radioactive isotopes such as ³ H and ¹⁴ C, or non-radioactive isotopes such as ² H and ¹³ C are present. It should be understood that it may contain or include compounds that: These isotopically labeled compounds can be used for metabolic studies (using ¹⁴ C), reaction kinetic studies (e.g. using ² H or ³ H), and detection or imaging techniques including drug or substrate tissue distribution analysis, for example positron emission tomography. It is useful for imaging (PET) or single-photon emission computed tomography (SPECT), or radiotherapy of patients. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, for example, using an appropriate isotopically labeled reagent in place of the previously used unlabeled reagent.

The present invention includes embodiments including all pharmaceutically acceptable salts of the compounds useful according to the invention provided herein. As used herein, “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include inorganic or organic acid salts of basic moieties, such as amines; These include, but are not limited to, alkali or organic salts of acidic residues, such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts of the parent compounds formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both; Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences , ^17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418] and Journal of Pharmaceutical Science , 66, 2 (1977), each of which is hereby incorporated by reference in its entirety. For example, preferred pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic moieties such as amines. For example, the salt may be a hydrochloride salt.

As used herein, the phrase "pharmaceutically acceptable" means that, within the scope of sound medical judgment, commensurate with a reasonable benefit/risk ratio, human and animal use without undue toxicity, irritation, allergic reaction, or other problems or complications may occur. refers to a compound, material, composition, and/or dosage form suitable for use in contact with the tissues of.

Unless otherwise indicated, as used herein, a “dose” or amount of a BCR-ABL inhibitor, such as Compound I, refers to the amount of the compound in free base or free acid form. For BCR-ABL inhibitors in salt form, the actual amount is adjusted based on the salt form used.

“Effective amount” refers to an amount sufficient to produce a beneficial or desired result. For example, a therapeutic amount is the amount that achieves the desired therapeutic effect. The amount may be the same or different from the prophylactically effective amount, which is the amount necessary to prevent the onset of a disease, condition, disorder, or syndrome or related symptom. An effective amount may be administered in one or more administrations, applications or dosages. The “therapeutically effective amount” (i.e., effective dosage) of a therapeutic compound varies depending on the therapeutic compound selected. The compositions can be administered from one or more times daily to one or more times a week, but also include less frequent administrations, such as those described herein, for example. Those of ordinary skill in the art will understand that certain factors, including but not limited to the severity of the subject's disease, condition, disorder, or syndrome, prior treatment, general health, and/or age, and other co-occurring diseases, conditions, disorders, or syndromes, may affect the subject. It will be appreciated that this may affect the dosage and timing required to effectively treat. Additionally, treatment of a subject with a therapeutically effective amount of a therapeutic compound described herein may include a single treatment or a series of treatments.

As used herein, the term “therapeutically effective amount” of a compound described herein refers to a method that causes a biological or medical response in a subject, such as improving symptoms, alleviating a condition, or slowing the progression of a disease. Refers to the amount of a compound that causes, delays, or prevents a disease, condition, disorder, sign, or syndrome. In one non-limiting embodiment, the term “therapeutically effective amount” when administered to a subject refers to a BCR-ABL mediated disease or disorder (e.g., chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and Refers to an amount of a compound described herein that is effective to at least partially alleviate, inhibit, prevent and/or ameliorate a leukemia selected from myeloid leukemia (AML).

As defined herein, “combination” means a fixed combination, a free (i.e., non-fixed) combination, or combined administration (e.g., capsule, tablet, sachet, or vial) in one unit dosage form (e.g., capsule, tablet, sachet, or vial). refers to a kit of parts for a combined administration, wherein Compound I and said one or more additional therapeutic agents can be administered independently or simultaneously within a time interval, in particular said time interval being such that the combination partners have a cooperative effect, e.g. For example, to show a synergistic effect.

As used herein, “add-on” or “add-on therapy” refers to a collection of therapeutic agents for use in a therapy, wherein the subject receiving the therapy receives a second treatment regimen of one or more different therapeutic agents in addition to the first treatment regimen. Start the first treatment regimen of one or more treatments before starting the treatment to ensure that not all treatments used in the regimen are started at the same time. For example, a BCR-ABL inhibitor, such as Compound I, is added to a patient who is already receiving at least one additional treatment such as imitinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib. A higher MR ^4.5 rate was achieved with asciminib add-on therapy compared to imatinib and nilotinib at week 48 (whereas a 4.5-log reduction (MR ^4.5 ) was seen for a BCR-ABL1/ABL ratio of ≤ 0.0032%) It turns out it can be done. Asiminib add-on therapy was tested in a phase 2, multicenter, open-label, randomized study of asiminib add-on to 1L imatinib versus continued imatinib versus switch to nilotinib (NCT03578367). Cumulative MR4.5 rates occurred earlier and were higher with asciminib add-on regimens than with imatinib and nilotinib. MR4.5 rates through week 48 were 19.0% with aciminib 40 mg QD add-on, 28.6% with aciminib 60 mg QD add-on, 0% with imatinib, and 14.3% with nilotinib.

As used herein, terms such as “co-administration” or “co-administration” are intended to include administering an additional therapeutic agent to a single subject (e.g., a subject) in need thereof, wherein the additional therapeutic agent includes Compound I and It is intended to include treatment regimens in which the additional therapeutic agents are not necessarily administered simultaneously and/or by the same route of administration. Each of the components of the presently described combination may be administered simultaneously or sequentially and in any order. Co-administration includes simultaneous administration, sequential administration, overlapping administration, spaced administration, and/or sequential administration and any combination thereof.

As used herein, the term “pharmaceutical combination” refers to a pharmaceutical composition resulting from the combination (e.g., mixing) of more than one active ingredient and comprising both fixed and free combinations of the active ingredients. do.

The term “fixed combination” means that the active ingredients are administered to a subject simultaneously in the form of a single entity or dosage form.

The term "free combination" (non-fixed combination) means that the active ingredients as defined herein are administered to a subject as separate entities simultaneously, together or sequentially, and in any order, without specific time restrictions, such administration Provides a therapeutically effective level of the compounds in the subject's body. In particular, as used herein (e.g., in any embodiment or any claim herein), reference to a combination comprising a) Compound I and b) one or more additional therapeutic agents refers to an “unfixed combination.” ", which may be administered independently or simultaneously within a time interval.

“Simultaneous administration” means that the active ingredients, as defined herein, are administered on the same day. The active ingredients may be administered simultaneously (for fixed or free combinations) or one at a time (for free combinations).

The term “sequential administration” may mean that only one of the active ingredients, as defined herein, is administered on any given day over a period of two or more consecutive co-administration days.

“Overlapping administration” means that during a period of two or more consecutive co-administration days, at least one day is administered simultaneously and at least one day only one of the active ingredients as defined herein is administered.

“Continuous administration” means a period of co-administration without any blank days. Sequential administration may be simultaneous, sequential, or overlapping as described above.

The term “dose” refers to a specific amount of drug administered at one time. The capacity may be indicated, for example, on the product package or on the product information leaflet.

Listed Embodiments (Embodiments 1 to 21):

Embodiment 1 : A method of treating a BCR-ABL mediated disease or disorder in a patient in need thereof, comprising: (i) a therapeutically effective amount of asciminib or a pharmaceutically acceptable amount thereof; A method comprising administering a pharmaceutical combination comprising a salt and (ii) a therapeutically effective amount of one or more additional therapeutic agents, wherein the pharmaceutical combination is administered with food.

Embodiment 2 : The method of Embodiment 1, wherein the BCR-ABL mediated disease or disorder is a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML).

Embodiment 3: The method of Embodiment 1 or 2, wherein asciminib or a pharmaceutically acceptable salt thereof is used in an add-on combination therapy to said one or more additional therapeutic agents.

Embodiment 4: The method of any one of Embodiments 1 to 3, wherein aciminib or a pharmaceutically acceptable salt thereof is administered to the patient in a single dose for a total daily dose of about 40 mg or 60 mg.

Embodiment 5 : The method of any one of Embodiments 1 to 4, wherein the one or more additional therapeutic agents are selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

Embodiment 6 : The method of claim 5, wherein the one or more additional therapeutic agents are imatinib.

Embodiment 7 : The method of any one of Embodiments 1 to 6, wherein imatinib is administered to the patient in a single dose for a total daily dose of about 400 mg.

Embodiment 8 : The method of any one of Embodiments 1 to 7, wherein the food is a low-fat meal.

Embodiment 9 : The method of any one of Embodiments 1 to 8, wherein the pharmaceutical combination is administered together sequentially or simultaneously.

Embodiment 10 : A method of treating a BCR-ABL mediated disease or disorder in a patient in need thereof, comprising a single dose, a total daily dose of about 40 mg or 60 mg. Administering asciminib or a pharmaceutically acceptable salt thereof and a single dose of imatinib in a total daily dose of about 400 mg, wherein the single dose of asciminib or a pharmaceutically acceptable salt thereof and the single dose of imatinib are low-fat. Administered with a meal.

Embodiment 11 : The method of Embodiment 10, wherein the dose of asciminib or a pharmaceutically acceptable salt thereof and the dose of imatinib are administered simultaneously.

Embodiment 12: The method of Embodiment 10 or 11, wherein asciminib or a pharmaceutically acceptable salt thereof is used in add-on combination therapy to imatinib.

Embodiment 13 : A method of treating a BCR-ABL mediated disease or disorder in a patient in need thereof, comprising administering a therapeutically effective amount of asciminib or a pharmaceutically acceptable salt thereof with food. A method comprising administering without.

Embodiment 14 : The method of Embodiment 13, wherein administering asciminib or a pharmaceutically acceptable salt thereof with food reduces bioavailability in the subject compared to administering asciminib or a pharmaceutically acceptable salt thereof without food. method.

Embodiment 15 : The method of Embodiment 13 or 14, wherein the BCR-ABL mediated disease or disorder is a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML).

Embodiment 16 : The method of any one of Embodiments 13 to 15, wherein asciminib or a pharmaceutically acceptable salt thereof is administered to the patient in divided doses at a total daily dose of about 80 mg, and the treatment of a BCR-ABL mediated disease or disorder. A method of treating a BCR-ABL mediated disease or disorder in a patient in need thereof comprising administering a therapeutically effective amount of asciminib or a pharmaceutically acceptable salt thereof without food.

Embodiment 17 : A method of treating a BCR-ABL mediated disease or disorder in a patient in need thereof, comprising: (i) a therapeutically effective amount of asciminib or a pharmaceutically acceptable amount thereof; A method comprising administering to a patient a salt and (ii) a therapeutically effective amount of one or more additional therapeutic agents, wherein asciminib or a pharmaceutically acceptable salt thereof is used in an add-on combination therapy to the one or more additional therapeutic agents.

Embodiment 18 : The method of Embodiment 17, wherein the one or more additional therapeutic agents are selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

Embodiment 19 : The method of Embodiment 17 or 18, wherein the one or more additional therapeutic agents are imatinib.

Embodiment 20: The method of any one of Embodiments 17-19, wherein asciminib or a pharmaceutically acceptable salt thereof is administered to the patient in a single dose for a total daily dose of about 40 mg or 60 mg.

Embodiment 21 : The method of any one of Embodiments 17-20, wherein imatinib is administered to the patient in a single dose for a total daily dose of about 400 mg.

Uses and Methods

Various embodiments of the methods and uses described herein are included below and elsewhere in this document. It will be appreciated that features specified in each embodiment may be combined with other specified features to provide additional embodiments.

In one embodiment, provided herein is a method of treating a BCR-ABL mediated disease or disorder in a subject in need thereof, comprising administering an effective amount of Compound I or a pharmaceutically acceptable dose thereof. and administering the salt without food. In one embodiment, provided herein is Compound I, or a pharmaceutically acceptable salt thereof, for use in treating a BCR-ABL mediated disease or disorder in a subject in need thereof, without food. do. In some embodiments, provided herein is the use of Compound I, without food, for preparing a medicament for treating a BCR-ABL mediated disease or disorder.

In another embodiment, treating or reducing the symptoms of a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML) in a subject in need thereof. Provided herein is a method of reducing , comprising administering an effective amount of Compound I or a pharmaceutically acceptable salt thereof without food. In one embodiment, use to treat a leukemia selected from chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML) in a subject in need thereof, without food. Provided herein is Compound I for: or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein is the use of Compound I for the manufacture of a medicament for treating a leukemia selected from chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), without food. provided.

In another embodiment, provided herein is a method of treating a BCR-ABL mediated disease or disorder in a subject in need thereof, comprising (i) administering an effective amount of Compound I or and (ii) administering a pharmaceutical combination of a pharmaceutically acceptable salt and (ii) an effective amount of one or more additional therapeutic agents. In one embodiment, Compound I, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents for use in treating a BCR-ABL mediated disease or disorder in a subject in need thereof. Pharmaceutical combinations of are provided herein. In some embodiments, provided herein is the use of a pharmaceutical combination of Compound I, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents for the manufacture of a medicament for the treatment of a BCR-ABL mediated disease or disorder.

In another embodiment, provided herein is a method of treating a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML) in a subject in need thereof. The method comprises administering a pharmaceutical combination of (i) an effective amount of Compound I, or a pharmaceutically acceptable salt thereof, and (ii) an effective amount of one or more additional therapeutic agents. In one embodiment, the compound is for use in treating a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML) in a subject in need thereof. Provided herein are pharmaceutical combinations of I or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Provided herein is the use of pharmaceutical combinations of , and one or more additional therapeutic agents.

In another embodiment, provided herein is a method of treating a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML) in a subject in need thereof. The method involves administering (i) an effective amount of Compound I or a pharmaceutically acceptable salt thereof and (ii) an effective amount of imatinib, nilotinib, dasatinib, bosutinib, or and administering a pharmaceutical combination of one or more additional therapeutic agents selected from natinib and bafetinib. In one embodiment, in a subject in need of treatment of a leukemia selected from chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), with food, preferably a low-fat meal, said Pharmaceutical combination of Compound I, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib for use in treating leukemia. Water is provided to the facility. In some embodiments, in combination with food, preferably a low-fat meal, for the manufacture of a medicament for the treatment of a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Provided herein is the use of a pharmaceutical combination of Compound I, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

In any of the embodiments described herein, Compound I, or a pharmaceutically acceptable salt thereof, may be administered to the patient in single or divided doses, for a total daily dose of about 20 mg to about 400 mg, measured in nasal salt equivalents. . In certain embodiments, Compound I is administered to the patient in single or divided doses for a total daily dose of about 80 mg. In another specific embodiment, Compound I is administered to the patient twice daily at a dose of about 40 mg.

In some embodiments, provided herein is a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition is a tablet. In another specific embodiment, the pharmaceutical composition is administered as whole or crushed tablets. In some embodiments, the pharmaceutical composition contains about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about Includes 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.

Provided herein are pharmaceutical compositions comprising Compound I, or a pharmaceutically acceptable salt thereof, for use in any of the embodiments described herein.

In any of the embodiments described herein, Compound I, or a pharmaceutically acceptable salt thereof, is administered orally to a subject in need thereof. In some embodiments, Compound I is in the form of tablets that are administered whole or subdivided, i.e., crushed (prior to administration). In certain embodiments, Compound I may be administered via a nasogastric tube, for example, if the patient is unable to swallow.

pharmaceutical composition

Compound I can be used as pharmaceutical compositions when combined with a pharmaceutically acceptable carrier. These compositions may contain, in addition to compound I, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers and other known substances. The characteristics of the carrier will vary depending on the route of administration. Pharmaceutical compositions for use in the compositions, uses and methods described herein may also contain at least one additional therapeutic agent for the treatment of a specific targeted disorder, disease, condition or syndrome. These additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with Compound I.

In certain embodiments, Compound I may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphate, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes. , such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes. , polyethylene-polyoxypropylene-block polymer, and wool paper. To enhance delivery of the compounds described herein, cyclodextrins, such as α-, β, and γ-cyclodextrins, or chemically modified derivatives, such as 2- and 3-hydroxypropyl-β-cyclodextrins, may be used. Hydroxyalkylcyclodextrins, or other solubilized derivatives, may also be used. Dosage forms or compositions can be prepared containing in the range of 0.005% to 100% of a chemical entity as described herein, with the balance consisting of non-toxic excipients. Contemplated compositions may contain from 0.001% to 100% of the chemical entities provided herein, from 0.1 to 95% in one embodiment, from 75 to 85% in another embodiment, and from 20 to 80% in a further embodiment. The actual methods of preparing such dosage forms will be known or apparent to those skilled in the art, see, for example, Remington: The Science and Practice of Pharmacy , ^22nd Edition (Pharmaceutical Press, London, UK. 2012).

Route of administration and composition components

In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof may be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration are buccal, dermal, intracervical, intranasal, intratracheal, enteral, epidural, interstitial, intraabdominal, intraarterial, intrabronchial, intrasynovial, intracerebral, intramedullary, intracoronary, intradermal, and intrabiliary. , intraduodenal, intrathecal, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, paranasal sinuses, intraspinal, Intrasynovial, intratesticular, intrathecal, intraluminal, intratumoral, intrauterine, intravascular, intravenous, intranasal, intranasogastric, oral, parenteral, percutaneous, peredural, intrarectal, respiratory (inhalation), subcutaneous, sublingual. , submucosal, topical, transdermal, transmucosal, rectal tract, ureter, urethra, and intravaginal. In certain embodiments, the preferred route of administration is the parenteral (e.g., intratumoral) route.

The compositions may be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared for injection as liquid solutions or suspensions, solid forms suitable for use in preparing solutions or suspensions upon addition of liquid prior to injection can also be prepared, and the preparations can also be emulsified. . The preparation of such formulations will be known to those skilled in the art in view of the present invention.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; Formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and flexible enough to be easily injected. It must also be stable under the conditions of manufacture and storage and preserved against the contaminating action of microorganisms such as bacteria and fungi.

The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, in the case of dispersions by maintenance of the required particle size, and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it will be desirable to include an isotonic agent, such as sugar or sodium chloride. Absorption of injectable compositions can be prolonged by using absorption delaying agents in the composition, such as aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various bactericidal active ingredients into a bactericidal vehicle containing the basic dispersion medium and the other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze-drying techniques, which produce powders of the active ingredient and any additional desired ingredient from a previously sterile-filtered solution.

Intratumoral injection is described, for example, in Lammers, et al., “ Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia . 2006 , 10 , 788-795].

In certain embodiments, the chemical entities described herein or pharmaceutical compositions thereof are suitable for local topical administration to the digestive tract or gastrointestinal tract, for example, intrarectal administration. Rectal compositions include, without limitation, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).

Pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g. PEG ointment), glycerin, glycerinized Gelatin, hydrogenated vegetable oil, poloxamer, petrolatum, a mixture of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide ( anoxid) SBN, vanilla essential oil, aerosol, paraben in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, carbopol, methyloxybenzoate, macrogol setoste. Aryl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane ( MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

In certain embodiments, suppositories contain the chemical entities described herein in a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum to release the active compound. It can be prepared by mixing with. In another embodiment, the composition for intrarectal administration is in the form of an enema.

In another embodiment, the compounds described herein, or pharmaceutical compositions thereof, are suitable for topical delivery to the digestive tract or gastrointestinal tract by oral administration (e.g., in solid or liquid dosage forms).

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the chemical entity may contain one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) agar agar, calcium carbonate, potato or tapioca starch, alginic acid, certain disintegrants such as silicates and sodium carbonate, e) dissolution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as cetyl alcohol and glycerol monostearate, h) kaolin and bentonite. An absorbent such as clay, and i) talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets and pills, the dosage form may also include buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols, etc.

In one embodiment, the composition is in the form of a unit dosage form, such as a pill or tablet, so that the composition may contain the chemical entities provided herein along with a diluent such as lactose, sucrose, dicalcium phosphate, etc.; Lubricants such as magnesium stearate and the like; and binders such as starch, acacia gum, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In other solid dosage forms, powders, marumes, solutions or suspensions (e.g. in propylene carbonate, vegetable oil, PEG, poloxamer 124 or triglycerides) are encapsulated in capsules (gelatin or cellulose based capsules). . One or more chemical entities or additional active agents provided herein may be administered in physically separate unit dosage forms, e.g., capsules (or tablets within capsules) with granules of each drug; Two-layer tablet; Two-part gel capsules, etc. are also contemplated. Enteric coated or delayed release oral dosage forms are also contemplated.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives that are particularly useful in preventing the growth or action of microorganisms. A variety of preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments, the excipients are sterile and generally free of undesirable substances. These compositions can be sterilized by conventional, well-known sterilization techniques. For excipients in various oral dosage forms such as tablets and capsules, sterilization is not necessary. USP/NF standards are usually sufficient.

In certain embodiments, the solid oral dosage form is one that chemically and/or structurally renders the composition such that the chemical entities are delivered to the stomach or lower stomach, such as the ascending colon and/or transverse colon and/or distal colon and/or small intestine. The above ingredients may additionally be included. Exemplary formulation techniques are described, for example, in Filipski, KJ, et al., Current Topics in Medicinal Chemistry , 2013 , 13 , 776-802 , which are incorporated herein by reference in their entirety.

Examples include upper gastrointestinal targeting technologies such as the Accordion Pill (Intec Pharma), floating capsules, and substances that can adhere to the mucosal wall.

Other examples include lower-gastrointestinal targeting techniques. To target different regions of the intestinal tract, several enteric/pH-responsive coatings and excipients can be used. Typically these materials are polymers designed to dissolve or decompose at specific pH ranges, selected based on the gastrointestinal region of desired drug release. These substances also function to protect acid-labile drugs from gastric juices or to limit exposure when the active ingredients may be irritating to the upper gastrointestinal tract (e.g., hydroxypropyl methylcellulose phthalate family, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other technologies include dosage forms that respond to the local flora of the gastrointestinal tract, pressure-controlled colonic delivery capsules, and Pulsincap.

Ocular compositions may include viscogen (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrins); Any of the following preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boronic acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)) It may include one or more without limitation.

Topical compositions may include ointments and creams. Ointments are semi-solid preparations, typically based on petrolatum or other petroleum derivatives. Creams containing selected active agents are typically viscous liquids or semi-solid emulsions, often oil-in-water or water-in-oil. Cream bases are typically washable with water and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes called the "internal" phase, generally consists of petrolatum and fatty alcohols such as cetyl or stearyl alcohol; The aqueous phase is generally, but not necessarily, larger in volume than the oil phase and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. As with other carriers or vehicles, the ointment base must be inert, stable, non-irritating, and non-sensitizing.

In any of the foregoing embodiments, the pharmaceutical compositions disclosed herein may comprise one or more of the following: lipids, interbilayer cross-linked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) )[PLGA]-based or polyanhydride-based nanoparticles or microparticles, nanoporous particle-supported lipid bilayers.

Dosage regimen and mode of administration

Dosage regimens are adjusted to provide the optimal desired response (eg, therapeutic response). Depending on the compound used, the disease, condition, disorder or syndrome targeted and its associated stages, the dosing regimen, i.e. the dosage and/or frequency of administration of the pharmaceutical composition comprising Compound I, may vary. Depending on the compound used, the disease, condition, disorder or syndrome and its associated stage, the dosing regimen, i.e. the dosage and/or frequency of administration of the pharmaceutical combination comprising a) Compound I and b) one or more additional therapeutic agents, may vary.

For administration of Compound I in a method of treating a BCR-ABL mediated disease or disorder, the dosage ranges from about 0.0001 to about 100 mg/kg of subject body weight, more typically from about 0.01 to about 30 mg/kg of subject body weight. In certain embodiments, Compound I is administered in a daily dose of about 20 mg to about 400 mg, about 40 mg to about 300 mg, about 80 mg to about 240 mg, about 40 mg to about 80 mg, about 80 mg. In certain embodiments, Compound I is administered in a daily dose of about 20 mg, about 40 mg, about 80 mg, or about 100 mg. In certain embodiments, Compound I is administered once daily. In other embodiments, Compound I is administered two, three or four times daily. In a preferred embodiment, Compound I is administered in a total daily dose of about 80 mg (administered in one or two divided doses). In some embodiments, Compound I is administered at a daily dose of 80 mg in two divided doses. In another embodiment, Compound I is administered at a daily dose of 40 mg once daily.

kit

Also included herein are kits for use in a method of treating or preventing cytokine release syndrome or cytokine storm syndrome, which may include Compound I in liquid or lyophilized form or a pharmaceutical composition comprising Compound I. Additionally, such kits may include a means for administering Compound I (e.g., syringes and vials, prefilled syringes, prefilled pens) and instructions for use. These kits may contain additional therapeutic agents (described elsewhere herein), for example for delivery in combination with Compound I.

The phrase “means of administration” includes any available device for systemically administering a drug to a patient (droppers, prefilled syringes, vials and syringes, injection pens, auto-injectors, i.v. drips and bags, pumps, etc.) It is used to indicate (but is not limited to). These items can be used to allow a patient to self-administer a medication (i.e., administer a medication under their own power), a caregiver to administer the medication to the patient, or a physician or other health care professional to administer the medication. You can.

Each component in a kit is usually sealed within an individual container, and all the various containers are in a single package along with instructions for use.

It should be understood that each embodiment may be combined with one or more other embodiments to the extent that such combinations are consistent with the description of the embodiment. Additionally, it should be understood that the embodiments provided above are understood to include all embodiments, including those embodiments that are the result of a combination of embodiments.

Other features, objects and advantages of the described methods and uses will be apparent from the detailed description and drawings and from the claims.

Example

The following examples illustrate the methods and uses described herein. However, this is not intended to limit the scope of the described methods and uses in any way. Other variations of the embodiments will be readily apparent to those skilled in the art and are encompassed by the appended claims.

Example 1: Flow analysis

To provide additional information on the food effect (FE) of asciminib (ABL001), an experimental in vitro study was conducted to determine the effect of bile components on the dissolution and penetration of a 40 mg dose of asciminib through artificial lipid membranes. carried out.

method

The donor compartment of a United States Pharmacopoeia, Method II (USP II) dissolution device (Distek corporation; NJ, USA) was incubated with low concentrations of bile salts (mimicking fasting conditions; fasting simulated intestinal fluid [FaSSIF]; 3 mM taurocholate/tau). rodeoxycholate, 0.2 mM phospholipid/lysophospholipid, pH 5.8), high concentration of bile salts (mimicking feeding intestinal conditions; feeding state simulated intestinal fluid [FeSSIF]; 10 mM taurocholate/taurodeoxycholate, 2 were filled with 900 mL maleate buffer containing either phospholipid/lysophospholipid, 0.8/5.0 mM oleate/glycerol monoleate, pH 6.0) or no bile salts (control; pH 6.5). FaSSIF and FeSSIF were prepared according to the manufacturer's instructions (Biorelevant. Available at Biorelevant.com (accessed March 2021)). In each of the three setups, two film-coated tablets of 20 mg of Asciminib (to achieve a total dose of 40 mg) were added to the buffer and maintained at 37°C with constant agitation (100 rpm). The receiver is then sealed by a 0.45 μm polyvinylidene fluoride membrane and an artificial lipid membrane and contains 12 mL of proprietary acceptor buffer (pION, Inc; Massachusetts, USA), which helps solubilize poorly soluble molecules at high concentrations. The compartment was inserted into the donor compartment. The dissolution and flux rates of asciminib were determined by measuring the concentration of asciminib in the donor and receiver compartments using a fiber optic probe. Two replicate experiments were performed per condition.

Discussion and Results

Fat intake has been shown to be positively correlated with the level of excreted bile acids, so the different compositions of bile were aimed to reflect feeding and fasting conditions (Trefflich et al. Associations between Dietary Patterns and Bile Acids -Results from a Cross-Sectional Study in Vegans and Omnivores. Nutrients 2019; 12(1)]). The dissolution rate of asiminib was fastest in a buffer containing a composition of bile salts, acids and lipids that mimics the fed state (FeSSIF), was slower in a buffer that mimics the fasting state (FaSSIF), and did not contain bile components. It was slowest in control buffer (Figure 1A). In contrast, the flux rate, or penetration, of asciminib through the artificial lipid membrane was lowest in fed state buffer (FeSSIF; 0.44 μg/min; 94.2% lysis) and in fasting state buffer (FaSSIF; 1.45 μg/min; 93.1% lysis). It was highest in the control buffer (2.66 μg/min; 82.3% dissolved) (Figure 1B).

Example 2: Phase I, single-center, two-arm, open-label study to evaluate the effect of imatinib and food on the pharmacokinetics of ABL001 (ashminib) in healthy volunteers.

An open-label, single-center Phase I study involving two distinct arms of healthy volunteers - a drug-drug interaction (DDI) study arm and a food effect (FE) study arm. Two study groups were enrolled independently of each other. Figure 2 is a schematic diagram of the treatment protocol.

The primary goals of this study are as follows:

DDI research group

To evaluate the effect of steady-state, multiple once-daily doses of 400 mg imatinib on the pharmacokinetics of a single dose of asciminib in healthy subjects under low-fat diet conditions.

FE research group

· To evaluate the FE for oral bioavailability of a single dose of asiminib in healthy subjects under various food conditions.

The endpoints (EPs) for the primary objectives are:

· Primary pharmacokinetic parameters: Cmax, AUCinf, and AUClast of asciminib

· Secondary pharmacokinetic parameters: Tmax, Tlast, AUC0-96h, lambda_z, T1/2, CL/F, Vz/F of v.

The secondary objectives of the study are:

DDI research group

· To evaluate the safety and tolerability of asciminib administered in combination with 400 mg imatinib under low-fat meal conditions in healthy subjects.

To evaluate the steady-state pharmacokinetics of 400 mg imatinib qd when administered in combination with a single dose of asiminib under low-fat meal conditions in healthy subjects.

FE research group

· To evaluate the safety and tolerability of a single oral dose of asciminib administered in healthy subjects under various food conditions.

The endpoints (EPs) for the secondary objectives are:

· Safety parameters such as occurrence of adverse events and serious adverse events, changes in hematology and blood chemistry values, vital signs and electrocardiogram.

· Secondary pharmacokinetic parameters: Tmax, Tlast, AUC0-96h, lambda_z, T1/2, CL/F, Vz/F of imatinib in DDI study group.

[Table 1]

study design

This study is a phase I, single-center, open-label, two-arm design. Each subject underwent a screening period (day -22 to -2), pretreatment period (baseline, day -1), treatment period, end of treatment visit, and 30-day safety follow-up (phone call).

Study group 1 (DDI study group)

The DDI study arm was a single-sequence, non-randomized arm that evaluated the effect of multiple doses of 400 mg imatinib administered with a low-fat meal on the pharmacokinetics (PK) of asciminib. This group consisted of a screening period of up to 21 days, a baseline period (day -1), and a treatment period of 13 days (days 1 to 13) and an additional safety period of 30 days after the last dose.

The first 3 subjects enrolled in the DDI group were scheduled to undergo an additional 3-day safety period following the end of the treatment visit. If safety outcomes were not observed in the first 3 subjects, the study was scheduled to continue enrolling the remaining 20 subjects. If a safety outcome meeting the criteria was observed in 1 of 3 subjects, an additional 3 subjects were scheduled to be enrolled and observed for a minimum period of 17 days before continuing with further enrollment in the study.

The treatment sequence for each subject within Study Group 1 is illustrated in Table 1 .

· Day 1: FDA low-fat meal was provided to subjects after at least 10 hours of fasting. A single dose of 40 mg asciminib was administered 30 minutes ± 5 minutes after the start of the meal.

· Days 5 to 8: Imatinib 400 mg was administered once daily with a meal and a glass of water.

· On day 5, blood samples for asciminib measurements were collected before administration of imatinib.

· Day 9: FDA low-fat meal was provided to subjects after at least 10 hours of fasting. A single dose of 400 mg imatinib and 40 mg asciminib was administered 30 minutes ± 5 minutes after the start of the meal.

· Days 10 to 12: Imatinib 400 mg was administered once daily with a meal and a glass of water.

[Table 1]

Study group 2 (FE study group)

The FE study arm was a crossover and randomized arm that evaluated the effect of different food conditions on the PK of asciminib. The study consisted of a screening period of up to 21 days, three baseline periods (one before each treatment period) and three treatment periods (each separated by a 7-day washout period) and an additional safety period of 30 days after the last dose. . Each subject underwent three treatment periods in which asciminib was administered under fasting conditions, with a low-fat meal, or with a high-fat meal.

Subjects were randomized to one of six treatment sequences, each treatment sequence having approximately 4 subjects. Each subject underwent three treatment periods, separated by a 7-day washout period, starting from the dosing date of the previous treatment period and ending with the baseline date of the next period (inclusive). End of treatment (EOT) assessments were performed 3 days after administration of the last dose of study treatment. A safety follow-up phone call was made 30 days after the last dose.

The treatment sequence for each subject within Study Group 2 is illustrated in Table 2 .

All subjects were scheduled to receive a single oral dose of 40 mg ashminib tablets under various food conditions on days 1, 8, and 15. All subjects received three doses of asciminib on days 1, 8, and 15.

[Table 2]

Dietary Requirements and Treatment Administration

During the screening process and throughout the study, subjects were instructed to avoid strenuous physical exercise and saunas, and to avoid alcohol, foods containing puffin seeds, caffeinated foods and beverages, and fruits known to inhibit CYP3A4 (e.g., grapefruit). , star fruit, cranberry, pummelo, pomegranate and Seville orange).

Study group 1 (DDI study group)

· Asciminib was administered in the morning after an overnight fast of ≥10 hours, 30 ± 5 minutes after the start of the FDA low-fat breakfast, with 240 mL of water.

· Imatinib was administered in the morning with a meal (standardized) and approximately 200 mL of water.

· On day 9, imatinib and asciminib were administered 30 ± 5 minutes after the start of a low-fat breakfast with 240 mL of water; Imatinib was administered first, followed immediately by asimiminib.

· No food was allowed for at least 4 hours after administration of asciminib and asiminib + imatinib, and for at least 1 hour on days when imatinib was given alone.

Study group 2 (FE study group)

Take asiminib in the morning with 240 mL of water after an overnight fast of ≥10 hours, under fasting conditions (i.e., without breakfast), 30 ± 5 minutes after the start of a low-fat breakfast, or after the start of a high-fat breakfast. Administered at 30 ± 5 minutes.

· For all three dietary conditions, participants were required to fast for 4 hours after administration of asiminib.

The composition of high-fat and low-fat meals was based on guidelines by the U.S. Food and Drug Administration (FDA), with high-fat meals containing 800 to 1000 calories, approximately 50% fat, approximately 35% carbohydrate, and approximately 15% protein; , low-fat meals contained ≤400 calories and <20% fat (FDA Guidance on Food Effect Studies, Dec 2002).

Ingestion of fluids was not permitted from 1 hour before dosing to 1 hour after dosing, except fluids taken with breakfast before dosing and water taken for study drug ingestion. Alternatively, water was taken as desired.

Participants were required to consume the entire contents of the provided meal within 30 minutes; Any instances of incomplete meal consumption were recorded. Asciminib and imatinib were administered as film-coated tablets.

group

Approximately 47 healthy adult male and female subjects meeting the inclusion and exclusion criteria were planned to be enrolled in the study.

Key inclusion criteria

Have a body mass index (BMI) between 18.0 and 29.9 kg/m ² in good health as determined by history, physical examination, vital signs and electrocardiogram (ECG), and absence of clinically significant findings from laboratory tests. Adult male and/or female (infertile or postmenopausal) subjects aged 18 to 55 years were enrolled in the study.

Main exclusion criteria

Heart or cardiac repolarization abnormalities, history of immunodeficiency disease, any surgical or medical condition that may interfere with absorption, distribution, metabolism, or excretion of study treatment, malignancy of any organ system (localized basal cell carcinoma of the skin) or history of cervical cancer other than in situ), and smoking.

Pharmacokinetic sampling and evaluation

In the DDI group, asciminib blood levels were assessed on days 1 to 5 and days 9 to 13, with samples taken pre-dose and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 10 and 12. (days 1 and 9), 24 and 36 hours post-dose (days 2 and 10), and 48, 72, and 96 hours post-dose (days 3 to 5 and days 11 to 13). .

· Imatinib PK was assessed over days 9 to 10 and days 12 to 13, with samples taken pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours post-dose ( on days 9 and 12), and 24 hours post-dose (days 10 and 13).

In the FE group, asciminib PK was assessed over days 1 to 4 of each of the three treatment periods, with samples taken pre-dose and post-dose 0.5, 1, 2, 3, 4, 6, 8, 10, and 12. (Day 1), 24 and 36 hours post-dose (Day 2), and 48, 72, and 96 hours post-dose (Days 3-4).

· Plasma concentrations of asciminib and imatinib were validated using a liquid chromatography-tandem mass spectrometry assay (LC-MS) with a dynamic range of 1.00 to 5000 ng/mL for asciminib and 20.0 to 10,000 ng/mL for imatinib. /MS) was used to determine. The method was validated for specificity, sensitivity, matrix effects, recovery, linearity, accuracy and precision, dilution feasibility, batch size and stability.

· For the analysis of asciminib, accuracy and precision for the LLOQ (1.00 ng/mL) were within ±5.0% bias and ≤8.0% CV, respectively. Based on intra- and inter-day evaluations, the accuracy (% bias) of the different internal standard solution samples ranged from -2.0 to 5.3%, and the precision ranged from 2.8 to 6.2% CV.

· For the analysis of imatinib, accuracy and precision for LLOQ (20.0 ng/ml) were within ±1.5% bias and ≤8.8%CV, respectively. Based on intra- and inter-day evaluations, the accuracy (% bias) of different internal standard solution samples ranged from -5.0% to 1.8%, and the precision ranged from 3.4% to 7.4% CV.

statistical analysis

Assuming 30% within-subject variability for the primary asciminib PK parameters (based on previously reported data17), providing adequate precision with 90% CI for the difference between test and reference parameters in log scale. A sample size of 18 participants per group was estimated, with the margin of error for the observed differences averaging 0.170 in the DDI group and 0.166 in the FE group (based on a paired-samples t-test using a two-tailed alpha level of 0.10). ). Considering a potential dropout rate of 20%, 23 participants were scheduled to be enrolled in the DDI group and 24 participants were enrolled in the FE group.

· PK analysis was based on all participants with at least 1 evaluable PK profile.

· In the DDI group, the PK profile of participants was such that they received all planned doses of imatinib on days 5 to 9 (day 9 profile); received all planned doses of imatinib on days 5 through 9 and at least two of the planned doses of imatinib on days 10 through 12 (day 12 profile); Received the scheduled dose of asciminib on each day; Pre-specified fasting requirements were adhered to; Patients were considered evaluable if they did not vomit within 4 hours after administration of asiminib and/or imatinib and provided at least 1 primary PK parameter for asiminib (asiminib PK profile) or imatinib (imatinib PK profile) .

· In the FE group, the asciminib PK profile of participants was such that they received 1 of the planned treatments; At least 75% of the meal was consumed for each feeding treatment; Pre-specified treatment administration requirements were followed; At least one primary Asciminib PK parameter was provided; Pre-specified fasting requirements were adhered to; Patients were considered evaluable if they did not vomit within 4 hours after administration of asciminib.

· The safety set in both of these groups included all participants who received ≥1 dose of study treatment. PK parameters were calculated from individual plasma concentration-time profiles using a non-compartmental method using Phoenix WinNonlin® (Pharsight, Mountain View, CA, USA) software version 6.4. PK parameters were summarized using geometric mean (Gmean), geometric coefficient of variation (GCV%), median, minimum, and maximum. Baseline characteristics are presented as frequencies and percentages for categorical data and median, minimum, and maximum values for continuous data. Missing values and values below the LLOQ were treated as missing values in the calculation of Gmean and GCV%. Formal statistical comparisons were performed on the primary asciminib PK parameters of Cmax, AUCinf, and AUClast. In the DDI group, formal statistical comparisons evaluated asciminib plus imatinib (test) versus asciminib alone (reference); A linear mixed model was fit to log-transformed PK parameters, with treatment as a fixed factor and participant as a random factor. In the FE group, formal statistical comparisons evaluated low-fat meal (test) versus fasting (baseline) and high-fat meal (test) versus fasting (baseline); A linear mixed model was fit to log-transformed PK parameters, with treatment, period and sequence included as fixed factors and participants nested within sequence as random factors. For all comparisons, point estimates and corresponding two-sided 90% confidence intervals (CIs) for the differences between test and baseline were calculated. Point estimates and CIs were inverse-log transformed to obtain point estimates and 90% CIs for the geometric mean (Gmean) ratio to the original scale. Characterization of secondary PK parameters was merely descriptive. All analyzes were performed using Statistical Analysis System (SAS) version 9.4.

safety

Monitored by evaluating physical examination, vital signs, height and weight, laboratory evaluation, cardiac evaluation, dietary records as well as collection of adverse events (AEs) at all visits.

○ AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 20.1, and the Common Terminology criteria for AEs [CTCAE] version 4.03.

· All clinical sample analyzes (hematology, blood chemistry) were performed by local laboratories.

result

Participant disposition and baseline characteristics

In total, 47 participants were enrolled in the study, of which 23 participants were enrolled in the DDI group and 24 participants were enrolled in the FE group.

· In the DDI group, the first 3 enrolled participants underwent an additional 3-day safety period after the end of the treatment visit (Sentinel administration). No safety outcomes were observed in these three participants, so the remaining 20 participants were enrolled. Twenty-two participants completed the DDI study, with all 22 participants receiving all scheduled doses of asciminib on days 1 and 9, and all eight doses of imatinib on days 5 through 12. One participant discontinued the study on day 5 and was excluded from the imatinib PK analysis set per protocol due to vomiting (grade 1 vomiting) within 4 hours of imatinib administration.

· In the FE group, all 24 enrolled participants (4 participants in each of 6 sequences) completed the study, and all participants received all planned doses of asciminib. One participant did not receive asciminib within 30 ± 5 minutes of the start of a meal during one of the treatment periods and was excluded from PK analysis.

· In the DDI group, median age at baseline was 47.0 years (range: 23-55 years) and median body mass index (BMI) was 25.3 (range: 19.1-29.5); 87.0% (20/23) of participants were male, 95.7% (22/23) were white, and 1 participant was African American.

· In the FE group, median (range) age was 44.5 (21-54) years, median BMI was 24.65 (range 19.7-29.4), 95.8% (23/24) participants were male, and all participants were white.

· One participant in the DDI group received concomitant paracetamol (500 mg QD) for headache on days 5 and 6. No concomitant medications were administered in the FE group.

PK analysis DDI group

The plasma concentration-time profile of asciminib revealed higher exposure when asciminib was administered with imatinib at steady-state compared to when asciminib was administered alone (Figure 3A).

· For both of these regimens, rapid absorption followed by a phase 2 decline after achieving Cmax was observed.

· Technical PK parameters indicated higher exposure to asciminib when administered in combination with imatinib compared to asciminib monotherapy (Table 1). Median Tmax was similar regardless of whether asciminib was administered alone (3.00 h; range 1.01 to 6.00 hours) or in combination with imatinib (3.00 h; range 1.94 to 4.00 hours). The Gmean of T1/2 was comparable between asciminib in the presence of imatinib (15.3 hours) and asciminib in the absence of imatinib (13.7 hours). The Gmean of asciminib clearance was 5.19 L/h when asciminib was administered together with imatinib, but was higher at 11.1 L/h when asciminib was administered alone.

Statistical comparison of primary asciminib PK parameters showed that with asciminib + imatinib, systemic aciminib exposure was approximately 2-fold increased compared to asciminib alone (Gmean ratio [90% CI] asiminib + imatinib vs. Asciminib, AUCinf 2.08 [1.93; 2.24]; AUClast 2.07 [1.92; 2.23]), and Cmax 1.6 (Gmean ratio [90% CI] 1.59 [1.45; 1.75]) (Table 3).

· Inter-subject variability (GCV%) for AUCinf and AUClast was comparable between asciminib alone and aciminib + imatinib (31.7-31.8% vs. 27.0-28.0), and for Cmax, aciminib alone was more effective than aciminib + imatinib. cases was higher (33.4% vs. 16.1%) (Table 4).

The plasma concentration-time profile of imatinib showed that co-administration of asciminib and imatinib resulted in slightly lower and slightly delayed imatinib exposure compared to imatinib administered alone.

· This effect was mainly observed during the absorption phase, and in the presence of asciminib, imatinib absorption was delayed (Figure 3B).

· Imatinib PK parameters using asciminib + imatinib versus imatinib alone were Gmean AUClast 29,600 ng x h/mL (GCV% 27.3%) vs. 33,600 ng x h/mL (GCV% 28.6%), respectively, Gmean AUC0-24h 30,100 ng x /mL (GCV% 27.4%) vs. 33,600 ng x h/mL (GCV% 28.6%), and the Gmean Cmax was 2020 ng/mL (GCV% 26.9%) vs. 2340 ng/mL (GCV% 29.5%), respectively. The median Tmax of imatinib was similar whether imatinib was administered with asciminib (3.01 [range 1.95 to 5.00] hours) or alone (3.00 [range 0.993 to 5.95] hours).

[Table 3]

[Table 4]

PK analysis (FE group)

The plasma concentration-time profile of asciminib under different food conditions showed that administration of asciminib with a meal, especially a high-fat meal, decreased exposure and delayed Tmax compared to fasting conditions (Figure 4).

Similarly, descriptive PK parameters showed lower exposure to asciminib when administered with a high- or low-fat meal compared to fasting conditions, with a greater reduction in exposure observed with the high-fat meal than with the low-fat meal (Table 5).

· Median Tmax (range) for asciminib was observed in the fasted state (2.01 [1.00 to 5.00] hours) compared to when administered with a high-fat meal (4.01 [1.00 to 8.00] hours) or a low-fat meal (3.00 [0.997 to 5.00] hours). It was longer when administered together with .

This observation was confirmed by a statistical comparison of asciminib PK parameters, which showed that the higher the fat content of the accompanying meal, the lower the exposure to asciminib (Table 6).

· For example, the Gmean ratio of AUCinf under low-fat meal conditions is 0.700 (90% CI 0.631 to 0.776), indicating a 30% reduction in exposure compared to fasting conditions.

· The Gmean ratio of AUCinf under high-fat meal conditions was 0.377 (90% CI 0.341~0.417), indicating a 62.3% reduction in exposure compared to the fasting state. Similar patterns were observed for AUClast and Cmax. Inter-subject variability for primary PK parameters was greater in the high-fat diet compared to low-fat diet (GCV% AUCinf 29.1%; AUClast 29.0%; Cmax 39.8%), or fasted conditions (GCV% AUCinf 35.5%; AUClast 35.2%; Cmax 39.7%). It was slightly higher when asciminib was administered with a meal (GCV% AUCinf 43.9%; AUClast 43.8%; Cmax 51.3%) (Table 5).

The observed food effect on the PK of asciminib in healthy individuals was also supported by the in vitro flux studies in Example 1, which showed how a 40 mg dose of asciminib dissolved and penetrated through artificial lipid membranes in different compositions. The effect of bile was evaluated.

[Table 5]

[Table 6]

safety

A single dose of 40 mg of asciminib was well tolerated in both study groups.

· Since this also applies to the DDI group's asciminib + imatinib surveillance dosing cohort, registration and treatment were expanded to the entire DDI cohort.

· In the DDI group, at least 1 AE was reported in 14 participants (60.9%). The most frequently reported AEs (≥5% of participants) were headache (n=5, 21.7%) and arthralgia, erythema, fatigue, hot flashes, nasal congestion, nasopharyngitis, and vomiting (n=2, 8.7% respectively).

· In the FE group, 11 participants (45.8%) had at least 1 AE; The most frequently reported AEs were oropharyngeal pain and rhinitis (n=2, 8.3%, respectively).

· In both study groups, all AEs were CTCAE grade 1 or 2 and there were no serious AEs. There were no clinically significant abnormalities in laboratory evaluation, vital signs, or ECG.

· In the DDI group, there was grade 3 neutropenia and grade 2 leukopenia in 1 participant.

· In the FE group, one participant had a grade 3 triglycerol lipase increase on day 2 of the fasting treatment period, which improved to normal on day 3. Another participant in the FE group had a grade 2 triglyceride increase on days 2 to 6 of the low-fat treatment period and on day 9 of the fasting period until EOT, and a grade 2 cholesterol increase on day 14 of the high-fat treatment period until EOT ( This returned to normal by day 31), and there was a grade 3 lipase increase on day 16 of the high-fat treatment period (which returned to normal by day 18). There were no other hematological or biochemical abnormalities of grade 3 or higher in the DDI or FE groups.

debate

This phase 1 study evaluated the effect of imatinib steady-state (under low-fat meal conditions) or various food conditions on the PK of a single dose of ashminib 40 mg (FMI tablet formulation) in healthy volunteers.

· Imatinib, and therefore the combination of asiminib + imatinib, was administered with meals to minimize gastric discomfort.

· The DDI study compared aciminib with and without imatinib when taken under the standard FDA low-fat meal conditions, and therefore the PK difference between the two situations is assumed to reflect the DDI between aciminib and imatinib.

· Asciminib + imatinib (taken with a low-fat meal) resulted in a 2-fold increase in asciminib systemic exposure (AUCinf and AUClast) and a 1.6-fold increase in asciminib Cmax compared to single-agent asciminib (taken under the food conditions above).

· Asciminib Tmax was not significantly different between Asiminib alone and Asiminib + Imatinib. The PK parameters of imatinib observed in this study were previously reported in a single-agent dose validation study of imatinib in CML patients (Peng et. al., Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 2005; 44(9): 879 -94]), and also observed when using imatinib + asciminib in CML patients (Cortes et. al.. Combination Therapy Using Asciminib Plus Imatinib in Patients With Chronic Myeloid Leukemia: Results From a Phase 1 Study. Presented at the European Hematology Association 24th Annual Congress; 2019; Amsterdam, the Netherlands], indicating that asciminib is unlikely to affect the PK of imatinib.

The observed effects of imatinib on asciminib exposure may be due to the fact that imatinib inhibits multiple pathways involved in the metabolism of asciminib.

Ashminib undergoes direct glucuronidation through several UDP-glucuronosyltransferases (UGT, mainly UGT2B7 and UGT2B17) and oxidation mainly through CYP3A4, and is also a substrate of breast cancer resistance protein (BCRP) And bile secretion contributes to its elimination (Tran et al., Disposition of asciminib, a potent BCR-ABL1 tyrosine kinase inhibitor, in healthy male subjects. Xenobiotica 2020; 50(2): 150-69]).

On the other hand, imatinib is an in vitro reversible moderate inhibitor of CYP3A4,14, an inhibitor of various UGTs with high potency against UGT2B17,23, and an inhibitor of BCRP and P-glycoprotein (D'Cunha et al., TKI combination therapy: strategy to enhance dasatinib uptake by inhibiting Pgp- and BCRP-mediated efflux. Biopharm Drug Dispos 2016; 37(7): 397-408]).

Importantly, the two-fold increase in asciminib exposure observed in studies using asciminib plus imatinib is not expected to negatively impact the safety profile of combination therapy as it did in CML patients, and the maximum tolerated dose of single-agent asciminib is It cannot be reached with a maximum dose of 200 mg twice daily (Hughes et al., Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med 2019; 381(24): 2315-26] ).

· Indeed, AE data from the study, including data from the surveillance dosing cohort, together with available safety data for the combination in CML patients, demonstrate that aciminib plus imatinib was well tolerated, with a safety profile comparable to that of a single agent. The safety profile of Asciminib 9 was consistent and there were no new safety signals.

The FE analysis results demonstrated that asciminib exposure is reduced when aciminib is administered with food. This effect became more pronounced the higher the fat content of the meal, and compared to fasting conditions, asiminib AUCinf and AUClast decreased by 30% in the low-fat meal and 62-63% in the high-fat meal. A delay in Tmax was also observed when asciminib was administered with food compared to fasting conditions, and as before for exposure, the change in Tmax increased with meal fat content. Most likely, the observed FE of asciminib is related to its sequestration by bile acids, especially when bile acid concentrations in the gastrointestinal tract are high, such as after a high-fat meal. This concept suggests that the higher the concentration of bile components in the buffer (i.e., the higher the fat content of the ingested meal20), the lower the flux rate of asciminib (i.e., longer Tmax) and lower the fraction of absorption of asciminib (in vivo). This is supported by the results of the flow analysis, which showed that

The magnitude of FE as well as the absolute measurements of Assiminib AUCinf, AUClast, and Cmax observed for Ashminib FMI tablet formulations in this study are consistent with previous results for FE using initial Ashminib formulations. Using these initial asciminib tablet formulations, asciminib exposure was reduced by approximately 30% and approximately 65% on low-fat and high-fat meals, respectively, compared to the fasting state, regardless of tablet modification.15 Based on the results of these FE studies, single agent Asciminib (FMI tablet formulation) should be administered on an empty stomach.

conclusion

Studies have shown that co-administration of asciminib (FMI tablet formulation) and imatinib results in a moderate (2-fold) increase in asciminib exposure and no change in imatinib exposure compared to asciminib alone when taken under the above dietary conditions. Therefore, when used in combination with imatinib (with food), aciminib is administered at 40 mg or 60 mg once daily, compared to the recommended single-agent dose of 40 mg twice daily on an empty stomach (Saglio et al., Randomized, Open-Label, Multicenter, Phase 2 Study of Asciminib (ABL001) As an Add-on to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase Who Have Not Achieved a Deep Molecular Response with Frontline Imatinib. ASH; 2019; 2019. p. (Supplement_1): 5910]). The food itself, especially high-fat foods, moderately (30-60%) reduces asciminib exposure depending on the fat content, possibly related to sequestration of asciminib by bile acids. Therefore, to avoid suboptimal exposure, it is recommended that asciminib be administered as a single agent on an empty stomach. In this study, the combination of asciminib + imatinib was well tolerated in healthy volunteers, consistent with preliminary clinical experience in CML patients. Overall, the study results suggest that coadministration of imatinib 400 mg once daily with asciminib 40 mg once daily under low-fat meal conditions has a favorable safety profile, and is at the recommended asciminib monotherapy dose (40 mg twice daily) under fasting conditions. appeared to result in a moderate increase in asciminib exposure, similar to that provided by . Currently, asciminib 40 mg or 60 mg once daily is being further investigated as an add-on therapy to imatinib in a phase 2 randomized trial in patients with chronic-phase CML who received first-line imatinib and did not achieve a deep molecular response (NCT03578367) .

All publications and patent documents cited herein are herein incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. The invention and its embodiments have been described in detail. However, the scope of the present invention is not intended to be limited to the specific embodiment of any process, manufacture, composition of matter, compound, means, method and/or step described herein. Various changes, substitutions and modifications may be made to the disclosed materials without departing from the spirit and/or essential characteristics of the invention. Accordingly, those skilled in the art will recognize that subsequent changes, substitutions and/or variations that perform substantially the same function or achieve substantially the same results as the embodiments described herein may be utilized in accordance with such related embodiments of the invention. will be easily recognized from the present invention. Accordingly, the following claims are intended to include within their scope variations, substitutions and variations of the processes, manufactures, compositions of matter, compounds, means, methods and/or steps disclosed herein. The claims should not be read as limited to the order or elements described unless stated to that effect. It should be understood that various changes in form and detail may be made without departing from the scope of the appended claims.

Claims (16)

A method of treating a BCR-ABL mediated disease or disorder in a patient in need thereof, comprising (i) a therapeutically effective amount of asciminib or a pharmaceutically acceptable salt thereof and (ii) ) A method comprising administering a pharmaceutical combination comprising a therapeutically effective amount of one or more additional therapeutic agents, wherein the pharmaceutical combination is administered with food. The method of claim 1 , wherein the BCR-ABL mediated disease or disorder is a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). 3. The method of claim 1 or 2, wherein asciminib or a pharmaceutically acceptable salt thereof is used in an add-on combination therapy to said one or more additional therapeutic agents. The method of claim 1 or 3, wherein aciminib or a pharmaceutically acceptable salt thereof is administered to the patient in a single dose for a total daily dose of about 40 mg or 60 mg. The method of any one of claims 1 to 4, wherein the one or more additional therapeutic agents are selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib. 6. The method of claim 5, wherein the one or more additional therapeutic agents are imatinib. 7. The method of any one of claims 1 to 6, wherein imatinib is administered to the patient in a single dose for a total daily dose of about 400 mg. 8. The method of any one of claims 1-7, wherein the food is a low-fat meal. 9. The method according to any one of claims 1 to 8, wherein the pharmaceutical combination is administered together sequentially or simultaneously. 1. A method of treating a BCR-ABL mediated disease or disorder in a patient in need thereof, comprising administering a single dose, a total daily dose of about 40 mg or 60 mg, of asciminib or the same. administering a total daily dose of about 400 mg of imatinib, the pharmaceutically acceptable salt and a single dose, wherein the single dose of asciminib or a pharmaceutically acceptable salt thereof and the single dose of imatinib are administered with a low-fat meal. How to become. The method of claim 10, wherein the dose of asciminib or a pharmaceutically acceptable salt thereof and the dose of imatinib are administered simultaneously. The method of claim 11, wherein asciminib or a pharmaceutically acceptable salt thereof is administered as add-on combination therapy. A method of treating a BCR-ABL mediated disease or disorder in a patient in need thereof, comprising administering a therapeutically effective amount of asciminib or a pharmaceutically acceptable salt thereof without food. Method, including. The method of claim 13 , wherein administering asciminib or a pharmaceutically acceptable salt thereof with food results in reduced bioavailability in the subject compared to administering asciminib or a pharmaceutically acceptable salt thereof without food. 15. The method of claim 13 or 14, wherein the BCR-ABL mediated disease or disorder is a leukemia selected from chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). 16. The method of any one of claims 13 to 15, wherein asciminib or a pharmaceutically acceptable salt thereof is administered to the patient in divided doses for a total daily dose of about 80 mg.